The Neuropathology Core (NP Core) under the direction of Dr. Stephen DeArmond will perform a service function, a hypothesis-generating function, and a hypothesis-testing function in molecular pathogenesis studies of prion diseases. The NP Core has contributed directly to approximately 100 publications on prion diseases. This NP Core will provide a full range of qualitative and quantitative neuropathology expertise including neurohistology for light microscopy, immunohistochemistry, and electron microscopy. Quantitative unbiased stereology and morphometrics are available as requested by the Projects. A full range of digital gross and microscopic photography and graphing are provided to investigators for notebooks and publications. Animals are autopsied, dissected, fixed or snap-frozen as needed, embedded in wax or plastic as needed, sectioned, and stained. For previous programs, the NP Core has pioneered development of techniques to identify PrPc and protease-resistant PrPSc in tissue sections. The NP Core maintains a bank of embedded and frozen animal tissues and a database with almost 10,000 animal entries in it to retrieve sections or blocks of tissues. The first Project proposes to generate 5 to 10 new recombinant PrP's folded into amyloid filaments per year. The NP Core must determine whether or not each construct causes a prion disease in transgenic (Tg) and wild-type mice and whether each serially transmits a similar disease to other Tg and wild-type mice. Those that do will have fulfilled the basic criteria of a mammalian prion. In addition, the NP Core must determine whether the neuropathological phenotype caused by a synthetic prion is sufficiently different to designate it a new prion strain. The fourth Project will test whether neurodegeneration caused by natural and synthetic prion strains follow the same stereotypical sequence of events during the second serial passage in Tg and wild-type mice. Neurohistological and immunohistochemical stains and histoblot analysis for protease-resistant PrPSc at 6 time-points during the course of disease will be processed in the NP Core. Animals will also be prepared and stained for Golgi silver impregnation-and synaptophysin immunohistochemistry. In addition, animals will be perfused with glutaraldehyde and paraformaldehyde, embedded in plastic, and prepared for routine electron microscopy. The NP Core will also help develop PrPSc immunogold histochemistry for electron microscopy.